Mammalian CNS neurons have a negligible capacity to regenerate after lesions. In contrast, neurons in the CNS of lower vertebrates and in the peripheral nervous system (PNS) of mammals are endowed with a high post-traumatic capacity to regenerate. In the goldfish visual system, the retinal ganglion cells regenerate severed axons and make functional connections with their appropriate targets. The regenerated axons become myelinated and form their normal pattern of synaptic contacts with their targets. In mammals, however, optic nerve injury leads to the death of most of the axotomized neurons and the failure of the surviving cells to regrow their axons.
The differences in regenerative capacity have been attributed to the different compositions of the respective cellular environments and to different responses to injury the non-neuronal cells display, which range from supportive and permissive to nonsupportive and hostile for regeneration. The same cell type may support or inhibit regeneration, depending on its state of maturity or differentiation. Astrocytes and oligodendrocytes are examples of cells in which such a dichotomy is manifested. In developing and in spontaneously regenerating nerves, these cells support (astrocytes) and permit (oligodendrocytes) growth. However, in nonregenerating adult mammalian nerves, astrocytes form the nonsupportive scar tissue; and the mature oligodendrocytes inhibit axonal growth. Maturation of these cells may be regulated differently during development than after injury.
Schnell et al, Nature, 343: 269-72 (1990), report that CNS white matter, cultured oligodendrocytes (the myelin producing cells of the CNS), and CNS myelin itself are strong inhibitors of neuron growth in culture, a property associated with defined membrane-bound surface proteins on myelin and oligodendrocytes. Monoclonal antibodies which neutralize the inhibitory effect of these proteins were implanted intracerebrally into rats. After transection of the cortico-spinal tract, massive sprouting occurred at the lesion site and fine axons and fascicles were observed up to 7-11 mm from the lesion.
Axotomized mammalian central neurons have been shown to regenerate their axons over long distances, if special conditions are provided by replacement of the optic nerve by a segment of a peripheral autologous nerve.
Prior work of the present inventor and others has shown that the CNS of lower vertebrates, specifically regenerating fish optic nerve, is a source of factors which, when applied at the appropriate time and in appropriate amounts to injured mammalian adult optic nerves, can support regenerative axonal growth. See Schwartz et al, Science, 228: 600-603 (1985); Hadani et al, Proc. Natl. Acad. Sci. U.S.A., 81: 7965-69 (1984); Lavie et al, Brain Res., 419: 166-173 (1987); Solomon et al, Metab. Pediatr. Syst. Ophthalmol., 11: 1-2, 31-2 (1988); and Cohen et al, Neurosci. Res., 22: 269-273 (1989).
Robbins et al, J. Immunol., 139, (8): 2593-7 (1987), have reported that stimulation of rat astrocytes in vitro resulted in the generation of a cytotoxic factor that is functionally similar to tumor necrosis factor. They also report that human recombinant tumor necrosis factor has cytotoxic activity directed against rat oligodendrocytes. Selmaj et al, Ann. Neurol., 23, (4): 339-46 (988) reported on the testing of recombinant human tumor necrosis factor (rhTNF) for its effect on myelinated cultures of mouse spinal cord tissue. They found that rhTNF induced delayed-onset oligodendrocyte necrosis and a type of myelin dilatation.
Despite substantial research efforts worldwide, no safe and effective means for causing CNS regeneration in mammals, and particularly humans, has yet been developed. Such a means, and particularly a pharmaceutical which can be injected at the site of desired regeneration would be greatly desirable in order to alleviate post-traumatic paraplegia or quadraplegia, blindness, deafness, surgically associated axotomy, etc.